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Preterm Parturition in Twins An Evidence-Based Approach

George R. Saade, M.D. Professor, Departments of Ob-Gyn and Cell Biology

Jennie Sealy Smith Distinguished Chair in Obstetrics and Gynecology

Chief of Obstetrics and Maternal Fetal Medicine

Director, Perinatal Research Division

The University of Texas Medical Branch

Dr. George Saade has no conflict of

interest related to the content of this

presentation.

Prediction

fFN and Prediction of Delivery Meta-analysis of 27 Studies

Leitich et al. Am J Obstet Gynecol 1999;180:1169-76

81-918680-9789Patients with PTL96-97973-6022Symptom free

81-968857-9676All studies

95% CIValue95% CIValue

Specificity (%)Sensitivity (%)

Delivery within 7 days

Likelihood Ratio (LR)

LR for a positive test

Likelihood for positive test with disease

Likelihood for positive test without disease

LR for a negative test

Likelihood for negative test with disease

Likelihood for negative test without disease

Likelihood Ratio (LR) Positive result

Condition + Condition -

Test + a b

Test - c d

Likelihood of test positive with condition

Likelihood of test positive without condition

a/(a+c)

b/(b+d)

sensitivity / (1-specificity)

LR+ =

LR+ =

LR+ =

Likelihood Ratio (LR)

Condition + Condition -

Test + a b

Test - c d

sensitivity / (1-specificity) LR+ =

LR- = (1-sensitivity)/specificity

Bayes Nomogram

Bayes Nomogram

Bayes Nomogram

Bayes Nomogram

Significance of LR

Cervicovaginal fFN Systematic Review

Honest et al. BMJ 2002;325:301-4

Asymptomatic

<34 weeks

<37 weeks

Symptomatic

7-10 days

<34 weeks

<37 weeks

0.1 0.5 1 5 10

Likelihood Ratio Neg Pos

fFN in Multiple Pregnancy Systematic Review

Conde-Agudelo. J Mat Fet Neo Med 2010;23:1365-76.

Asymptomatic Multiples



Asymptomatic Women



Twins with Threatened Preterm Birth



Pretest and Posttest Probabilities










What To Do With the Result?

Negative fFN and Probability of Delivery Plaut et al. Am J Obstet Gynecol 2003;188:1588-95

Negative fFN and Probability of Delivery Plaut et al. Am J Obstet Gynecol 2003;188:1588-95

Rapid Bedside fFN Prediction of Preterm Delivery

Coleman et al. Am J Obstet Gynecol 1998;179:1553-8

fFN and/or cervical dilatation > 1 cm for the predicting

delivery within 10 days in symptomatic women

fFN Cervix > 1 cm

fFN pos and/or

cervix > 1 cm

Sensitivity (%) 65 71 82Specificity (%) 85 87 76PPV (%) 41 46 36NPV (%) 94 95 96Likelihood Ratio

for positive testfor negative test

4.30.41

5.50.33

3.40.24

Rapid Bedside fFN Effect on Length of Hospital Stay

Plaut et al. Am J Obstet Gynecol 2003;188:1588-95

fFN and Physician Behavior RCT

Grobman et al. Am J Obstet Gynecol 2004;191: 235-40

LR for CL <25 mm in Predicting Delivery <34 wks Honest et al. Ultrasound Obstet Gynecol 2003;22:305-22

Knowledge of CL and FFN Effect on Management of Threatened PTL - RCT

Ness et al. Am J Obstet Gynecol 2007;197:426.e1-426.e7.





CL Assessment in Twins Systematic Review of Randomized Trials

Berghella et al. Cochrane Review 2013

PTB < 36 weeks

CL Assessment in Twins Systematic Review of Randomized Trials

Berghella et al. Cochrane Review 2013

Prevention

Prior to Labor

Home Uterine Activity Monitoring Dyson et al. N Engl J Med 1998;338:15-9

Weekly Contact

(n = 798)

Daily Contact

(n = 796)

HUAM

(n = 828)

Preterm birth (%)

< 37 weeks

< 32 weeks

14

4

13

5

14

4

Birthweight

< 2,500 gm

< 1,500 gm

26

4

26

4

28

4

# of unscheduled visits* 1.2 + 1.5 1.8 + 2 2.3 + 2.3

Received tocolytics (%)# 12 14 19

PTL < 35 weeks

%

dilatation (cm)

23

1.8 + 2

22

1.5 + 1.2

27

1.4 + 1.2

* P < 0.002 for all between group comparisons

# P < 0.01 for HUAM vs weekly or daily contact

No benefit noted even when twins or patient diagnosed with PTL < 35 weeks analyzed

separately.

Home Uterine Activity Monitoring Dyson et al. N Engl J Med 1998;338:15-9

Weekly Contact

(n = 798)

Daily Contact

(n = 796)

HUAM

(n = 828)

Preterm birth (%)

< 37 weeks

< 32 weeks

14

4

13

5

14

4

Birthweight

< 2,500 gm

< 1,500 gm

26

4

26

4

28

4

# of unscheduled visits* 1.2 + 1.5 1.8 + 2 2.3 + 2.3

Received tocolytics (%)# 12 14 19

PTL < 35 weeks

%

dilatation (cm)

23

1.8 + 2

22

1.5 + 1.2

27

1.4 + 1.2

* P < 0.002 for all between group comparisons

# P < 0.01 for HUAM vs weekly or daily contact

No benefit noted even when twins or patient diagnosed with PTL < 35 weeks analyzed

separately.

Hospitalization and Bed Rest for Multiples Systematic Review

Crowther. Cochrane Review 2010

Birth weight



Delivery < 34 weeks



Birth weigth < 2500 g



No effect on other outcomes

No benefit in twins or triplets only

No benefit in asymptomatic women with

cervical dilatation

Oral Beta-mimetics for Twins Systematic Review

Yamasmit. Cochrane Review 2012

Delivery < 37 weeks

Cerclage for Short Cervix Berghella et al. Obstet Gynecol 2005;106:181-9

17P for Prevention of Recurrent PTB ACOG Committee Opinion. Nov 2003

Further studies needed for other high

risk factors

When used, restrict to documented

history of previous spontaneous birth

less than 37 weeks

Multiple gestation was an exclusion in

original trial

Progesterone for PTB Prevention in

Twins Systematic Review

Norman et al. Lancet 2009; 373: 2034–40

Higher Dose of Vaginal Progesterone RCT Serra et al. BJOG 2013;120:50-7.

Eligibility

Singleton or twin gestation

Gestational age between 20 and 25

weeks

Transvaginal sonographic cervical

length <15 mm

Asymptomatic (without signs or

symptoms of preterm labor or ROM)

Treatment

Daily vaginal capsules containing 200

mg micronized progesterone versus

placebo

From 24 to 33 6/7 weeks

Vaginal Progesterone in Twins with Short Cervix Meta-analysis

Klein et al. Ultrasound Obstet Gynecol 2011;38:281-7.

Delivery < 34/35 weeks

IPD Meta-analysis of Vaginal Progesterone for

Asymptomatic Short Cervix Romero et al. Am J Obstet Gynecol 2012;206:124.e1-19

Singleton vs Twins

IPD Meta-analysis of Vaginal Progesterone for

Asymptomatic Short Cervix Romero et al. Am J Obstet Gynecol 2012;206:124.e1-19

Twins

17P (500 mg 2x/wk) in Twins with Short Cervix RCT

Senat et al. Am J Obstet Gynecol 2013;208:194.

Goya et al. Lancet 2012;379:1800-6

Pessary in Multiple Gestation RCT - Overall Result

Liem et al. Am J Obstet Gynecol 2013

Pessary in Multiple Gestation RCT – Subgroup CL < 25th%ile (38 mm)

Liem et al. Am J Obstet Gynecol 2013

PTB <32 wk

RR 0.43 (0.21-0.89)

NN morbidity

RR 0.41 (0.19-0.90)

MFMU Trial Study Design

Standard three-arm trial of women with twin

gestations and cervical shortening identified at

16-24 wk randomized to either:

1. Vaginal progesterone

2. Arabin pessary

3. Vaginal placebo

Twin Management in MFMU Sites (N=21)

Routine CL screening

– 11 sites assess CL in most twins

Definition of short CL

– Varies from 15 – 30 mm; 25 mm

Progesterone

– 5 sites offer vaginal progesterone for short CL; others individualize

Pessary

– Used only at 2 sites

Prevention Prior to Labor Recommendations

Testing and treatment for asymptomatic

bacteriuria

Testing and oral treatment (5 – 7 days)

for abnormal vaginal flora in

asymptomatic at-risk women

No CL screening

Vaginal progesterone if find cervix <20

mm before 24 weeks

Prevention

Symptomatic

Hydration for PTL Effect on Delivery <37 wks

Boulvain et al. The Cochrane Library 2003

Hydration for PTL Effect on Use of Tocolytics


Hydration for PTL Effect on Time to Delivery


Systematic Review of Tocolytics Effect on Delay of Delivery

Gyetvai et al. Obstet Gynecol 1999;94:869-77

MgSO4 OR 95%CI

Delivery <24 hrs 1.07 0.54 – 2.15

Delivery <48 hrs 0.52 0.26 – 1.05

Delivery <7 d 1.54 0.85 – 2.82

Nifedipine vs -mimetics Meta-Analysis

Tsatsaris et al. Obstet Gynecol 2001;97:840-7

Effect on # of patients OR 95% CI

Delay >48 hrs

Interruption of Rx

RDS

Admission to NICU

Neonatal death

520

590

497

493

651

1.52

0.12

0.57

0.65

1.51

1.03 – 2.24

0.05 – 0.29

0.37 – 0.89

0.43 – 0.97

0.63 – 3.65

Systematic Review of Tocolytics Maternal Harm

Berkman et al. Am J Obstet Gynecol 2003;188:1648-59

-mimetics Ca-channel

blockers

Magnesium Atosiban Placebo

Systematic Review of Tocolytics Effect on Perinatal and Neonatal Outcome

Gyetvai et al. Obstet Gynecol 1999;94:869-77

Berkman et al. Am J Obstet Gynecol 2003;188:1648-59

None shown to improve perinatal or

neonatal outcome

Maintenance Tocolysis Meta-Analysis

Sanchez-Ramos et al. Am J Obstet Gynecol 1999;181:484-90

Effect on # of patients OR 95% CI

Preterm Delivery

Recurrent PTL

RDS

IVH

NEC

Admission to NICU

Perinatal death

1498

1491

1273

1119

1001

861

1393

0.95

0.81

1.06

1.36

1.90

1.03

1.73

0.77 – 1.17

0.64 – 1.03

0.72 – 1.55

0.70 – 2.64

0.64 – 5.61

0.75 – 1.42

0.80 – 3.72

Maintenance with Beta-mimetics Effect on SPTB <37 weeks

Honest H et al. Health Technol Assess 2009;13(43)

Terbutaline Pump Maintenance Prevention of PTB <34 & <37 wks


Maintenance Ca Channel Blockers Effect on PTB <37 wks


RCOG Clinical Guideline Grade A Recommendations

No. 1(B), October 2002

It is reasonable not to use tocolysis

Tocolysis should be used if few days

gained would be put to good use

Ritodrine no longer best choice

Atosiban or nifedipine preferable

Maintenance tocolysis not

recommended for routine practice

Indomethacin vs Nifedipine Author Agent N Percent undelivered

48 hours 7 days

Gyetvai12- 3 studies Indomethacin 49 88 83

Morales4 Indomethacin 49 90

Besinger34 Indomethacin 22 83 67

King29- 1-2 studies Indomethacin 34 88.2 67.6

Total 88.0 (N= 154) 74.6 (N=105)

Lyell3 Nifedipine 100 92

Cararach42 Nifedipine 39 76.9 66.7

Weerakul43 Nifedipine 45 68.8

Tsatsaris44- 9 studies Nifedipine 268 75.3

King20- 4-9 studies Ca Channel blocker 383 80.7 69.0

Total 79.5 (N=835) 68.8 (N=422)

Choice of Tocolytic

Cervical Dilation

>4 cm <4 cm

Magnesium Gestational Age

<32 weeks >32 weeks

Indomethacin Nifedipine

Choice of Tocolytic

Cervical Dilation

>4 cm <4 cm


<32 weeks >32 weeks


Choice of Tocolytic

Cervical Dilation

>4 cm <4 cm


<32 weeks >32 weeks


Choice of Tocolytic

Cervical Dilation

>4 cm <4 cm


<32 weeks >32 weeks


Choice of Tocolytic

Cervical Dilation

>4 cm <4 cm


<32 weeks >32 weeks


Antibiotics in Intact Membrane Effect on Preterm Birth

King & Flenady. The Cochrane Library 2003

Antibiotics in Intact Membrane Effect on Delivery <48 hrs or <7 d King & Flenady. The Cochrane Library 2003

Antibiotics in Intact Membrane Effect on Neonatal Sepsis


Antibiotics in Intact Membrane Effect on Perinatal Mortality


7 Year Follow up

of ORACLE II Kenyon et al. Lancet 2008;372:1319–27

Antibiotics in pPROM Effect on Major Cerebral Abnormality

Kenyon et al. The Cochrane Library 2003

Co-amoxiclav in pPROM Effect on Incidence of NEC


Erythromycin vs Co-amoxiclav

in pPROM Effect on Incidence of NEC


Prevention of Preterm Birth Recommendation for Symptomatic Patients

Confirm labor – Clinical

– Transvaginal ultrasound

No tocolysis after 32 – 34 weeks

First-line tocolytic – Indomethacin (50 mg po followed by 25 mg Q 6o)

– Nifedipine (20-40 mg po followed by 20 mg Q 6o)

No maintenance tocolysis

Ampicillin + Erythromycin for pPROM

Interventions to Improve Neonatal

Outcome

Magnesium for Fetal

Neuroprotection

Observational Studies Nelson & Grether. Pediatrics 1995;95:263-269

Randomized Controlled Trials

Intent for neuroprotection

– MagNET Mittendorf et al. Lancet 1997;350:1517-8.

– ACTOMgSO4 Crowther et al. JAMA 2003;290:2669-76.

– PreMag Marret et al. Br J Obstet Gynecol 2007;114:310-8.

– BEAM Rouse et al. 2008.

Other Intent

– MAGPIE Br J Obstet Gynecol 2007;114:289-99.

Meta-analysis of all RCT CP or Death

Costantine et al. Obstet Gynecol 2009;114:354–64

Meta-analysis of all RCT Any CP


Meta-analysis of all RCT Death or Moderate-Severe CP


Meta-analysis of Neuroprotection RCT CP or Death


Considerations

To prevent one case of cerebral palsy

– Treat 56 (overall)

– Treat 46 (<30 weeks)

To prevent one eclamptic convulsion

– Treat 71 with severe disease

– Treat 400 with mild disease

Conclusions

Not a tocolytic

Use for imminent delivery (within 24 hrs)

or pPROM

Limit to less than 32 weeks (best less

than 28 weeks)

Caution

UTMB Protocol Indications

Likely delivery within 2- 24 hours at 23-32 weeks with patient not candidate for tocolysis. Examples of such cases

– PPROM at 23 to 32 weeks

– Preterm labor at 24-32 weeks with cervix between 4 and 8 cm dilatation

– Severe IUGR (with abnormal Doppler) requiring delivery

– Abnormal Testing (Late, REDF, etc) requiring delivery within 24 hours

– Chorioamnionitis requiring delivery

UTMB Protocol Exclusions

– Imminent delivery within < 2 hours

– Cervix > 8 cm

– PPROM < 23 weeks or > 32 weeks gestation

– Preeclampsia / Eclampsia on Mag

– Prior magnesium sulfate therapy within 12 hours

– Major fetal anomalies

– Delay delivery deemed detrimental to mom

• Severe preeclampsia with unstable HELLP

• Maternal respiratory compromise

• Cardiac arrest or heart Block

• Severe bleeding requiring immediate delivery

UTMB Protocol Exclusions

– Expedited delivery is required or delayed delivery

deemed detrimental to fetus

• Unstable abruption- bleeding

• Fetal distress- Category III

• Unstable previa

• Prolapsed umbilical cord

– Maternal contraindication to magnesium sulfate

• Myasthenia gravis

• Pulmonary hypertension

• Cardiac diseases (Class II-IV)

• Severe acute pulmonary dz- pneumonia, acute

asthma, ARDS, edema

• Serum creatinine > 1 mg/dL

UTMB Protocol Administration

• Dose- 6 gm loading then 2 gm/hour (40 gm of magnesium

sulfate in 500 cc of NS)

• Duration of treatment- until delivery or 12 hours whichever

comes first then discontinued.

• Resume treatment if still less than 32 weeks and delivery

deemed likely

– If < 6 hours since discontinuation of magnesium sulfate, restart

infusion at 2 gm/hour

– If > 6 hours since discontinuation of magnesium sulfate, load with 6

gm then 2 gm/hour

– Do not retreat if it will delay delivery that is detrimental to mom or

fetus

• Once on magnesium for neuroprotection, do not use any

tocolytic agents. These patients are not candidate for

tocolysis

Thank you

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